The present invention relates to a sleep-inducing preparation comprising a prostaglandin derivative as an effective ingredient.
Since prostaglandin (hereinafter referred to as xe2x80x9cPGxe2x80x9d) exhibits various important physiological actions in a trace amount, the syntheses of the derivatives from natural PGs and the biological activities have been investigated with the intention of a practical use as medicines and have been reported in many literatures.
Particularly, PGs have been reported on the various central nervous actions and have been clarified as to the intracerebral content, biosynthesis, metabolic pathway, their intracerebral localizations and changes with growth or aging, and there has been taken an interest in the relation of PGs with sleep and wake. Among them, PGD2 has been known as an intracerebral humoral factor which controls the occurrence or maintenance of sleep, and it was made clear that the sleep induced by PGD2 in monkeys is undistinguished from the spontaneous natural sleep in brain wave or behavior (Proc. Natl. Acad. Sci. USA, vol. 85, pp. 4082-4086 (1988)), therefore this compound is expected as a compound having a novel sleep-inducing action.
However, PGD2 derivatives including PGD2 are presently unpractical due to the problems concerning the effect and the stability as a drug.
As a result of the extensive studies, the present inventors have found that the prostaglandin derivatives having a triple bond between the 13- and 14-position represented by the following formula (I) have a characteristic sleep-inducing action, and thereby the present invention has been accomplished.
That is, the present invention is directed to a sleep-inducing preparation which comprises as an effective ingredient a prostaglandin derivative represented by Formula (I): 
wherein X is a halogen atom, Y is a group represented by (CH2)m, a cis-vinylene group or a phenylene group, Z is an ethylene group, a trans-vinylene group, OCH2 or S(O)nCH2, R1 is a C3-10 cycloalkyl group, a C3-10 cycloalkyl group substituted with C1-4 alkyl group(s), a C4-13 cycloalkylalkyl group, a C5-10 alkyl group, a C5-10 alkenyl group, a C5-10 alkynyl group or a bridged cyclic hydrocarbon group, R2 is a hydrogen atom, a C1-10 alkyl group or a C3-10 cycloalkyl group, m is an integer of 1 to 3, and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.
Further, the present invention is directed to a sleep-inducing preparation which comprises as an effective ingredient a prostaglandin derivative represented by Formula (I) wherein X is a chlorine atom or a bromine atom, Y is a group represented by (CH2)m or a cis-vinylene group, Z is an ethylene group, a trans-vinylene group, OCH2 or S(O)nCH2, R1 is a C3-10 cycloalkyl group or a C4-13 cycloalkylalkyl group, R2 is a hydrogen atom or a C1-10 alkyl group, m is an integer of 1 to 3, and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention is directed to a sleep-inducing preparation which comprises as an effective ingredient a prostaglandin derivative represented by Formula (I) wherein X is a chlorine atom or a bromine atom, Y is a group represented by (CH2)m or a cis-vinylene group, Z is OCH2, R1 is a C3-10 cycloalkyl group or a C4-13 cycloalkylalkyl group, R2 is a hydrogen atom or a C1-10 alkyl group, and m is an integer of 1 to 3, or a pharmaceutically acceptable salt thereof.
Still furthermore, the present invention is directed to a sleep-inducing preparation which comprises as an effective ingredient a prostaglandin derivative represented by Formula (I) wherein X is a chlorine atom or a bromine atom, Y is a group represented by (CH2)m or a cis-vinylene group, Z is SCH2, R1 is a C3-10 cycloalkyl group or a C4-13 cycloalkylalkyl group, R2 is a hydrogen atom or a C1-10 alkyl group, and m is an integer of 1 to 3, or a pharmaceutically acceptable salt thereof.
Still furthermore, the present invention is directed to a sleep-inducing preparation which comprises as an effective ingredient a prostaglandin derivative represented by Formula (I) wherein Y is a group represented by (CH2)m, Z is SCH2, R1 is a C3-10 cycloalkyl group, R2 is a hydrogen atom or a C1-10 alkyl group, and m is an integer of 1 to 3, or a pharmaceutically acceptable salt thereof.
Still furthermore, the present invention is directed to the above-mentioned prostaglandin derivative or the pharmaceutically acceptable salt for use as an ingredient for sleep-inducing preparation.
Still furthermore, the present invention is directed to a method for sleep-inducing comprising administering a pharmaceutically effective amount of the above-mentioned prostaglandin derivative or the pharmaceutically acceptable salt to a human.
In the present invention, the halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Examples of the C3-10 cycloalkyl group are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.
Examples of the C3-10 cycloalkyl group substituted with C1-4 alkyl group(s) are a methylcyclopropyl group, a methylcyclohexyl group and an ethylcyclohexyl group.
Examples of the C4-13 cycloalkylalkyl group are a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclohexylmethyl group, a cyclohexylethyl group and a cycloheptylmethyl group.
The C5-10 alkyl group refers to a straight or branched alkyl group, and examples thereof are a pentyl group, a hexyl group, a heptyl group, an octyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 1-methylhexyl group, a 2-methylhexyl group, a 2,4-dimethylpentyl group, a 2-ethylpentyl group, a 2-methylheptyl group, a 2-ethylhexyl group, a 2-propylpentyl group, a 2-propylhexyl group and a 2,6-dimethylheptyl group.
The C5-10 alkenyl group refers to a straight or branched alkenyl group, and examples thereof are a 3-pentenyl group, a 4-hexenyl group, a 5-heptenyl group, a 4-methyl-3-pentenyl group, a 2,4-dimethylpentenyl group, a 6-methyl-5-heptenyl group and a 2,6-dimethyl-5-heptenyl group.
The C5-10 alkynyl group refers to a straight or branched alkynyl group, and examples thereof are a 3-pentynyl group, a 3-hexynyl group, a 4-hexynyl group, a 1-methylpent-3-ynyl group, a 2-methylpent-3-ynyl group, a 1-methylhex-3-ynyl group and a 2-methylhex-3-ynyl group.
Examples of the bridged cyclic hydrocarbon group are a bornyl group, a norbornyl group, an adamantyl group, a pinanyl group, a thujyl group, a caryl group and a camphanyl group.
The C1-10 alkyl group for R2 refers to a straight or branched alkyl group, and examples thereof are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a 2-ethylpropyl group, a hexyl group, an isohexyl group, a 1-ethylbutyl group, a heptyl group, an isoheptyl group, an octyl group, a nonyl group and a decyl group.
Examples of the pharmaceutically acceptable salt are salts with alkali metal (e.g. sodium or potassium), alkali earth metal (e.g. calcium or magnesium), ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, a tetraalkyl ammonium and tris(hydroxymethyl)aminomethane.
According to the sleep-inducing preparation of the present invention, in view of the sleep-inducing effect, Y is preferably an ethylene group or cis-vinylene group, Z is preferably OCH2 or SCH2, and R1 is preferably a cycloalkyl group in Formula (I) of the prostaglandin derivatives as the effective ingredient.
Some of the compounds of Formula (I), according to the present invention, are known in WO94/02457, WO94/08959, Japanese Patent Kokai Hei-6-192218, Japanese Patent Kokai Hei-7-242622, Japanese Patent Kokai Hei-7-242623, Japanese Patent Kokai Hei-7-233144, Japanese Patent Kokal Hei-7-285929, Japanese Patent Kokai Hei-8-208599, Japanese Patent Kokal Hei-7-233143, Japanese Patent Kokal Hei-9-286775, Japanese Patent Kokai Sho-58-8059, Japanese Patent Kohyo Sho-60-501813 and Japanese Patent Kohyo Sho-60-500787.
On the other hand, the compounds wherein Z is S(O)CH2 and S(O)2CH2 can be prepared by a reaction of the compounds wherein Z is SCH2 using an oxidant such as sodium metaperiodide in a solvent such as methanol.
According to the present invention, representative compounds of Formula (I) are described as follows:
The compounds in the present invention can be administered orally or parenterally such as intravenously or nasally. For example, they can be administered orally in the form such as tablets, dusting powders, granules, powders, capsules, solutions, emulsions or suspensions, each of which can be prepared according to conventional methods. As the dosage forms for intravenous administration, there are used aqueous or non-aqueous solutions, emulsions, suspensions or solid preparations to be dissolved in a solvent for injection immediately before use. Furthermore, nasal administration can be performed by spraying quantitatively a solution or a powder (hard capsules) containing the drug into the nasal cavity by use of a dedicated nasal dropper or sprayer. The compounds in the present invention can be formulated into the form of the inclusion compounds with xcex1-, xcex2- or xcex3-cyclodextrin, or methylated cyclodextrin. The dose is varied by the age, body weight, etc., but it generally is from 1 ng to 1 mg/day per adult.
The present invention makes it possible to provide a sleep-inducing preparation which is sufficiently effective and remarkably stable.